Porphyria cutanea tarda (PCT) is due to the inhibition of a specific hepatic enzyme, uroporphyrinogen decarboxylase (UROD), which leads to marked porphyrin accumulation in the liver. The disease develops in some individuals who are predisposed by certain environmental and inherited susceptibility factors, and is manifested by skin photosensitivity and liver damage. Susceptibility factors include hepatitis C, alcohol use, smoking, iron overload, HIV, estrogens and an inherited partial deficiency of UROD. Why PCT develops in only a few individuals with these susceptibility factors, many of which are relatively common, is not known, and additional influences.- most likely additional inherited differences - remain to be identified. PCT itself causes liver damage, and genetic factors that promote its development may play a role in other liver diseases, such as those induced by hepatitis C and alcohol. We will investigate the novel hypothesis, based on previous work in laboratory models, and limited human studies, that polymorphisms in phase I and phase II enzymes, such as cytochrome P450 enzymes (CYPs) and glutathione transferases (GSTs) may contribute to developing PCT. Their substrates and products may influence oxidative stress in hepatocytes, and hepatic CYPs play a role in generating a specific UROD inhibitor. At least 120 patients with well- documented PCT and matched controls will participate in a case-control study and be phenotyped in detail, including characterization of known susceptibility factors. Hospital controls will be matched 1:1 and community controls 2:1 with PCT patients. DNA samples will be prepared from patients and controls and genotyped for specific CYP1A1, CYP1A2, CYP2E1, GSTM1 and GSTT1 polymorphisms, and the results analyzed as related to phenotype (e.g. presence or absence of PCT, clinical features, known susceptibility factors, treatment response and history of relapse). DNA samples and lymphocytes from these patients and matched controls, and information regarding clinical phenotype (including known susceptibility factors) will be stored as a repository for future, multi-center studies of additional genetic influences on the development of PCT. We will utilize resources of the UTMB General Clinical Research Center and the Texas Gulf Coast Digestive Diseases Center. This study and projects which follow will lead to a better understanding of PCT and also contribute to knowledge about how agents such as alcohol and hepatitis C interact with genetic factors in causing human liver diseases. [unreadable] [unreadable] [unreadable]